ARTIGO/ARTICLE
Revista da Sociedade Brasileira de Medicina Tropical 39(2):146-151, mar-abr, 2006
Neurological disease in HIV-infected patients in the era of highly
active antiretroviral treatment: a Brazilian experience
Doença neurológica em pacientes infectados pelo HIV na era da terapia
anti-retroviral altamente ativa: uma experiência brasileira
Jacqueline Ferreira de Oliveira1, Dirceu Bartolomeu Greco2, Guilherme Correa Oliveira3,
Paulo Pereira Christo1, Mark Drew Crosland Guimarães4
and Rodrigo Corrêa-Oliveira3
ABSTRACT
To study characteristics of neurological disorders in HIV/AIDS patients and their relationship to highly active antiretroviral
treatment, a cross-sectional study was conducted in an infectious disease public hospital in Belo Horizonte, Brazil, between
February 1999 and March 2000. Of the 417 patients enrolled, neurological disease was observed in 194 (46.5%) and a new
AIDS-defining neurological event developed in 23.7% of individuals. Toxoplasmosis (42.3%), cryptococcosis meningitis (12.9%)
and tuberculosis (10.8%) were the most common causes of neurological complications. The majority (79.3%) of patients
were on highly active antiretroviral treatment and these individuals using HAART showed higher CD4 cell counts (p = 0.014)
and presented stable neurological disease (p= 0.0001), although no difference was found with respect to the profile of
neurological complications. The neurological diseases continue to be a frequent complication of HIV/AIDS and infections are
still its main causes in Brazil, even in the highly active antiretroviral treatment era.
Key-words: HIV infection. AIDS. Neurological disease. Highly active antiretroviral treatment. Brazil.
RESUMO
Com o objetivo de estudar as doenças neurológicas em pacientes HIV/AIDS e sua relação com a terapia anti-retroviral
altamente ativa, foi realizado estudo transversal em hospital público de doenças infecciosas de Belo Horizonte, Brasil, no
período de fevereiro de 1999 a março de 2000. Doença neurológica foi observada em 194 (46,5%) dos 417 indivíduos
incluídos e um novo episódio de doença neurológica definidora de AIDS ocorreu em 23,7% pacientes. Toxoplasmose
(42,3%), criptococose (12,9%) e tuberculose (10,8%) foram as principais causas de complicações neurológicas. A maioria
dos pacientes estava em uso de terapia anti-retroviral altamente ativa (79,3%) e esses indivíduos apresentaram maiores
contagens de linfócitos CD4 (p = 0,014) e maior freqüência de doença neurológica clinicamente estável, embora não
tenha havido diferença no perfil etiológico das complicações neurológicas. As doenças neurológicas continuam sendo
causas freqüentes de complicações da infecção pelo HIV/AIDS no Brasil, e a despeito da terapia anti-retroviral altamente
ativa, as infecções são ainda a principal etiologia das doenças do sistema nervoso.
Palavras-chaves: Infecção pelo HIV. SIDA. Doença neurológica. Terapia anti-retroviral altamente ativa. Brasil.
1.Hospital Eduardo de Menezes, Minas Gerais Hospital State Foundation, Belo Horizonte, MG. 2. Infectious Disease Service, Federal University of Minas Gerais
School of Medicine, Belo Horizonte, MG. 3. René Rachou Research Center, Oswaldo Cruz Foundation,Belo Horizonte, MG. 4. Department of Preventive and Social
Medicine, Federal University of Minas Gerais School of Medicine, Belo Horizonte, MG, Brazil.
Address to: Dra. Jacqueline Ferreira de Oliveira. Hospital Eduardo de Menezes. R. Dr. Cristiano Rezende 2213, Bonsucesso, 30622-020 Belo Horizonte, MG, Brasil.
Tel: 55 31 3383-8000, Fax: 55 31 3383-8526
e-mail: [email protected]
Recebido para publicação em 18/4/2005
Aceito em 25/1/2006
146
Oliveira JF et al
Neurological diseases occur frequently in individuals
infected with human immunodeficiency virus type – 1 (HIV-1)
and significantly affect their functional capacity, quality of
life and survival 14 18.
Early in the AIDS epidemic, neurological manifestations were
reported in 31% to 70% of all HIV1-infected patients19 33. Since
the highly active antiretroviral therapy (HAART) has emerged
however, multiple studies confirm a decrease in the incidence,
as well as a change in the presentation of central nervous system
(CNS) opportunistic infections and HIV associated dementia
(HAD) in industrialized countries7 11 15 16 20 21 26 30 36 37.
The impact of HAART on the HIV-associated neurological
disorders in developing countries still remains unclear.
Limited access to antiretroviral therapy in addition to specific
social-epidemiological conditions may produce a different
picture compared with the United States and Europe 2 24 27 39 .
In Brazil, a public health program was implemented in
1996 and provides free treatment to approximately 141,000
Brazilians with HIV infection 13 34. The effectiveness of the
program has already been demonstrated in the reduction of
AIDS related death27 34 and in a significant decline of certain
opportunistic infections 12 . Particularly in the field of
neurological disease, however, there is limited information
available. Most of the reports concerning the epidemiology
of HIV/AIDS neurological disorders in Brazil were published
prior to combined antiretroviral therapy 3 6 25 28 29 38.
In this study, we determined the frequency of neurological
disorders in an AIDS reference center in Brazil in the era of
HAART, described the spectrum of its main etiologies and
assessed the relationship between neurological diseases and
antiretroviral therapy.
MATERIAL AND METHODS
This cross-sectional study was conducted in a public
reference infectious disease hospital, Hospital Eduardo de
Menezes (HEM), the main tertiary hospital for HIV/AIDS
patients in the metropolitan area of Belo Horizonte (2.8
million inhabitants), Brazil, during the period of February,
1999 to March, 2000.
Patients. All adult HIV1-infected individuals admitted were
evaluated for current neurological manifestations and/or
previous AIDS-defining neurological diagnosis. Neurological
manifestations were defined as the presence of any altered state
of consciousness, cognitive abnormalities, motor and/or
sensitivity disturbances, behavior disorders, ataxia and dizziness,
cranial nervous deficit, seizures or headaches other than primary.
AIDS-defining neurological diagnoses were defined according
to the Centers for Disease Control, CDC/93 criteria4.
All medical records were reviewed for information regarding
demographic variables, sexual behavior, CD4+ cell counts and
HIV-1 viral load. Plasma HIV-1 RNA, expressed as copies/ml was
measured by nucleic acid sequence based amplification (NASBA),
with a level of detection of 80-copies/ml. Previous access to
HIV related medical care prior to hospitalization and
antiretroviral regime use in the 6 months prior to the evaluation
period were examined. The antiretroviral treatment was classified
in (1) no therapy; (2) dual therapy - patients using a combination
of 2 nucleoside transcriptase reverse inhibitors; (3) HAARTpatients using three antiretroviral drugs defined as a combination
of protease inhibitors (PI) or non nucleoside transcriptase
reverse inhibitors (NNITR) plus two nucleoside transcriptase
reverse inhibitors.
The individuals included in the study were classified
into groups according to their neurological disease
profile: (i) stable, i.e., patients with previous AIDS-related
neurological disorders, but who were free of neurological
symptoms; (ii) symptomatic, i.e., patients with signs or symptoms
of neurological manifestations at admission or at any time during
hospitalization. The symptomatic group was considered as new
or recurrent cases of neurological disease, respectively, if the
neurological diagnosis has been previous established.
The criteria for HIV-associated dementia were defined
according to the AIDS Task Force of the American Academy of
Neurology1. Primary cerebral lymphoma was diagnosed in
patients with unifocal enhancing mass lesions shown by
computerized tomography (CT) and positive findings in brain
biopsy. Toxoplasmosis encephalitis was defined in patients with
focal signs and symptoms, multifocal enhancing mass lesions in
CT and improvement of the symptoms after initiation of antitoxoplasma treatment (therapy with pyrimethamine and
sulfadiazine or clindamycin). Cryptococcal meningitis was
considered in the presence of typical symptoms and detection of
the cryptococcal antigen or direct identification of cryptococcal
organisms and a positive culture in cerebrospinal fluid (CSF).
Tuberculosis was presumed by typical symptoms of basal
meningitis or focal sign and symptoms in addition to
predominance of lymphocytes with high protein levels in CSF
followed by the improvement of symptoms and CSF alterations
after tuberculostatic treatment or a positive culture for
Mycobacterium tuberculosis in CSF. Progressive multifocal
leukoencephalopathy (PML) was defined in patients with
progressive focal signs and symptoms, a decline in cognitive
function and multifocal non-enhancing white matter lesions in
the CT. Cytomegalovirus (CMV) encephalitis was defined as the
presence of diffuse neurological signs and symptoms and CT nonspecific findings such as ventriculomegaly and periventricular
enhancement associated with a positive protein chain reaction
(PCR) for CMV DNA in CSF. Herpes simplex virus (HSV) and
varicella zoster virus (VZV) encephalitis were considered in the
presence of diffuse or focal signs and symptoms, non-enhancing
focal lesions in the CT with typical pox lesions or herpes zoster.
The detection of these viruses in CSF by PCR analysis was not
available. Neurosyphilis diagnosis was based on the combination
of reactive serological tests and abnormalities of CFS cell count or
protein or a reactive VDRL-CSF with or without manifestations5.
Bacterial meningitis was diagnosed by detection of bacteria in
GRAM stain and positive latex for bacterial antigens or culture in
CSF. Other diagnoses considered were psychiatric disturbances
and toxic-metabolic encephalopathy. Despite extensive
147
Revista da Sociedade Brasileira de Medicina Tropical 39(2):146-151, mar-abr, 2006
investigation some neurological disorders were considered
unspecific when no cause could not be determined.
Data analysis. Statistical tests: chi-square test with Yates
correction and the student t- test, were performed using
EpiInfo 2000 version 1.12 software ceded by the Centers for
Disease Control and Prevention. For all analyses p values
< 0.05 were considered statistically significant.
Ethics. The Ethical Committee on Human Experimentation
of the University of Minas Gerais School of Medicine and the
Eduardo de Menezes Hospital approved the study.
RESULTS
Between February 1999 and March 2000, a total of 417
HIV1-infected patients were admitted to the HEM, of which
194 (46.5%) presented neurological disease; 80.9% with
symptomatic and 19.1% with stable neurological disease,
respectively. Among the symptomatic patients (n=157), new
AIDS-defining neurological events were observed in
99 (63.1%) patients, recurrence was observed in 25 (15.9%),
and 33 (21%) individuals developed non-AIDS defining or
nonspecific lesions. The overall proportion of new AIDSdefining neurological diagnoses was 23.7% (99/417).
The descriptive characteristics of those with neurological
disorders can be seen in Table 1. Age ranged from 18 to 65
years old (mean age = 35.8 ± 0.6), 135 patients (69.6%) were
male, 142 (89.3%) had a low education level (≤ 8 years) and
98 (80.3%) acquired HIV through sexual transmission. The mean
T lymphocyte CD4 cell count was 93.9 X 106 /l (SD=110.6)
Table 1 - Sociodemographic, laboratorial and therapeutic characteristics of
HIV-infected patients (n=194) with neurological disease at Hospital Eduardo
de Menezes, Belo Horizonte, Brazil, 1999-2000.
Characteristics
Gender
male
female
Mean age (years)
Sexual exposure to HIV
Education level (< 8 years)
CD4+ cell count (x106 /l)
Viral load count (copies/mm3)
HIV diagnosis:
pre-admission
at hospital
Previous outpatient care (n=148)
yes
no
Antiretroviral therapy (n=146)
yes
no
Antiretroviral regime (n =111)
HAART
dual
no information
* Numbers vary due to missing values
148
No
%*
135
59
69.6
30.4
98
142
80.3
89.3
Mean (SEM)
35.8 ± 0.6
93.9 ± 110.6
28,854 ± 602.3
156
38
80.4
19.6
115
33
77.7
22.3
111
35
76.1
23.9
88
12
11
79.3
10.8
9.9
and mean plasma HIV-1 RNA was 28,854 copies/mm 3
(SD=602.3). Thirty-eight (19.6%) individuals with
neurological disease were diagnosed with HIV-1 infection at
the hospital, while 156 (80.4%) patients presented a previous
well-defined diagnosis, among which 115 (77.7%) were
under HIV outpatient care prior to admission. Finally, 111
(76.1%) had been on antiretroviral therapy in the 6 months
prior to the evaluation period, among which, 88 (79.3%)
had been on HAART, 12 (10.8%) on dual therapy and for
11 (9.9%) individuals there was no information regarding
the antiretroviral scheme used.
Infections occurred in 151 (77.8%) patients. Toxoplasmosis
was the most frequent opportunistic infectious disease (42.3%),
followed by cryptococcosis meningitis (12.9%) and tuberculosis
(10.8%) (Table 2). HIV-associated dementia was observed in
9 (4.6%) cases in this series and primary CNS lymphoma in
only one (0.5%) patient. Despite extensive neurodiagnostic and
neuroimaging evaluation, no etiology was defined in 16 (8.3%)
of the individuals.
Table 2 - Causes of neurological disease in HIV-1 infected patients (n=194) at
Hospital Eduardo de Menezes, Belo Horizonte, Brazil, 1999-2000.
Etiology
No
%
Infection
toxoplasmosis
82
42.3
cryptococcal meningitis
25
12.9
tuberculosis
21
10.8
PML
7
3.6
CMV encephalitis
3
1.6
bacterial
2
1.0
syphilis
2
1.0
VZV encephalitis
2
1.0
HSV encephalitis
1
0.5
≥ 2 infectious diseases
6
3.1
Non-defined etiology
16
8.3
HIV dementia
9
4.6
Toxic and metabolic encephalopathy
7
3.6
Psychiatric disorders
5
2.6
Other causes
5
2.6
Neoplasic disease
1
0.5
PML - progressive multifocal leukoencephalopathy. CMV - cytomegalovirus. HSV - human
simplex virus. VZV - human zoster virus
Symptomatic neurological HIV-infected patients presented
statistically significant lower T CD4 cell counts (≤ 100 cells/mm3)
(p= 0.045), were less likely to have used previous HIV
outpatient care (p=0.005) or to have used antiretroviral
treatment (p=0.001), compared to stable patients. There
were no differences which respect to gender, age, educational
level and viral load between the two groups (Table 3).
The variables that were associated with being on HAART were
lymphocyte T CD4+ cell count ( >200 cells/mm3) (p=0.014)
and stable neurological profile (p=0.0001) (Table 4). There
were no differences between the antiretroviral schemes with
respect to viral load, overall AIDS-defining neurological disease
or overall opportunistic infection. However, the numbers were
too small for proper statistical assessment.
Oliveira JF et al
Table 3 - Clinical and laboratorial conditions associated with stable or
symptomatic neurological disease in HIV-infected patients at Hospital Eduardo
de Menezes, Belo Horizonte, Brazil, 1999-2000.
Symptomatic
Stable
neurological disease neurological disease
(n = 157) %*
(n = 37) %*
Variable
Gender
male
108
female
49
Age
< 35
74
≥ 35
83
Education level (n = 159)
≤ 8 years
111
> 8 years
16
CD4 cell count (n = 139)
80
< 100 x 106 /l
≥ 100 x 106 /l
31
HIV viral load (n = 107)
< 80 copies/mm3
8
80 – 55,000 copie/mm3
38
≥ 55,000 copies/mm3
37
Previous outpatient care (n = 148)
yes
82
no
31
Antiretroviral therapy (n=146)
yes
76
none
34
* Numbers vary due to missing values
P-value
68.8
31.2
27
10
73.0
27.0
0.77
47.1
52.9
17
20
45.9
54.1
0.96
87.4
12.6
31
1
96.9
3.1
0,10
72.1
27.9
14
14
50.0
50.0
0.045
9.6
45.8
44.6
1
14
9
4.2
58.3
37.5
0.48
88.4
27.4
33
1
97.1
2.9
0.005
69.1
30.9
35
1
97.2
2.9
0.001
Table 4 - Analyses of HIV1-infected patients (n=194) with neurological disease
according to some clinical and laboratorial conditions and the antiretroviral
scheme at Hospital Eduardo de Menezes, Belo Horizonte, Brazil, 1999-2000.
HAART
No therapy
Variable
no *
no *
p-value
CD4 cell count (n = 94)
< 200 x 106 /l
55
26
0.014
≥ 200 x 106 /l
12
1
HIV viral load (n = 80)
< 55,000 copie/mm3
33
15
0.96
≥ 55,000 copie/mm3
21
11
Neurological disease profile
symptomatic
54
34
0.0001
stable
34
1
AIDS-defining neurological disease**
yes
66
26
0.88
no
22
9
Cause of AIDS-defining
neurological disease (n= 92)
opportunistic infection
65
24
0.19
non-infectious
1
2
* Numbers vary due to missing values. ** CDC Centers for Disease Control and Prevention:
revised classification system for HIV infection and expanded surveillance of definition for
AIDS among adolescents and adults4.
DISCUSSION
This is the first study on neurological disorders in the
HAART era in Brazil. The most important finding of the study
was that neurological disorders continue to be a frequent
complication in HIV1-infected patients. The observed
proportion (46.5%) of cases was very similar to publications
prior to 1996. In two clinical series between 1989 and 1991,
Vecino et al 38 found a prevalence of 60.4% for neurological
disease and Puccioni-Sohler et al28 demonstrated a frequency
of 26% of neurological complications in two distinct Brazilian
university hospitals. Our results were also in agreement to
that found a prevalence of 42.7% for neurological
manifestations in São Paulo9.
Brazil is the first developing country to have implemented a
large-scale universal antiretroviral distribution program and
approximately 141,000 patients now receive antiretroviral
treatment through the public health system. This study describes
the overall characteristics of neurological disorders in HIV after
universal access to HAART in Brazil. In this context, the current
findings may indicate an apparent contradiction. Considering
that 76% of neurological patients were on antiretroviral treatment
and nearly 80% of them on HAART, a lower prevalence of
neurological disorders would be expected. Although a complete
explanation is difficult, the results presented here could be
partially biased by the severity of the patients’ disease conditions.
Data were collected from a hospitalized population, presumably
more immunosuppressed than outpatients. As demonstrated by
the low mean T CD4+ cell count (93.9 x 106 cell/l), these patients
indeed presented end-stage AIDS and were expected to develop
more opportunistic complications, including CNS diseases.
The possibility of partial or deferred immune reconstitution in
response to HAART should also be considered. The drug regimen
and the onset the antiretroviral therapy were also not investigated.
It is possible that patients who had recently started HAART may
have been subject to a higher risk of a neurological event.
Other factors such as a poor adherence to HAART, a less
potent regimen, a failing regimen, or a recent rescue scheme
may have contributed to the increased risk of neurological
complications.
We characterized the profile of patients who were developing
neurological disease in the era of combined antiretroviral
treatment. Individuals with advanced immunodeficiency,
T CD4+ cell counts < 100/mm3 (p = 0.045), those without
previous HIV outpatient care (p=0.005) and patients not
receiving antiretroviral therapy (p=0,001) showed a statistically
significant probability for the manifestation of neurological
symptomatic disorders. The percentage of patients on HAART
was also significantly higher in the group of neurological stable
patients (p=0.0001), compared to the symptomatic patients. This
same profile has been observed in the developed world, where
central nervous system diseases still occur, particularly in
individuals who do not take antiretroviral drugs, but even in those
who do take theses agents8 15 20 22 31.
Infections were the most common cause of neurological
disease and occurred in 151 (77.8%) patients, which suggests
that the spectrum of neurological disease etiologies has not
changed in Brazil. Our results are consistent with Chimelli at al6
in a pre-HAART report on 252 autopsy cases who observed a
65.4% incidence of opportunistic infections and Fragoso et al9
who found an 80% rate of opportunistic neurological disease in
149
Revista da Sociedade Brasileira de Medicina Tropical 39(2):146-151, mar-abr, 2006
an early-HAART Brazilian series. It is probable that geographic
and socioeconomic factors interfere with the evolution of the
HIV-1 infection, possibly by enhancing the risk of exposure
to infectious agents. Reports from India17 32 and Mexico10 23
confirm the predominance of infectious neurological
disorders over HIV dementia and neoplasic disease.
Toxoplasmosis was still the most common opportunistic
infection in the central nervous system (42.3%) and cryptococcal
meningitis was the second (12.9 %). The present study could
not confirm the low frequencies of toxoplasmosis (2.2% to 8%)
and of cryptococcosis (0.8% to 4.9%) documented by Masliah
et al21 Sacktor et al31, Mascke et al20, Jellinger et al15, Neuenburg
et al26, and Gray et al11 in the HAART era in the developed world.
Tuberculosis was the third cause (10.8%) of opportunistic
neurological infection in this study in agreement with statistics
from tropical areas and in developing countries 17 32. The
frequency of HIV associated dementia and primary CNS lymphoma
were very low in this Brazilian series, probably misdiagnosed
because the concomitance of opportunistic infections and the
limited access to cerebral biopsy and modern imaging.
We believe there are several limitations to the current study.
Only HIV-infected inpatients were considered. It is unknown
whether similar results would be obtained in other groups, such
as outpatient care or with a higher T CD4+ cell count and higher
adherence. Data related to antiretroviral regimens and compliance
was not always available. The low specificity of neurological signs
and symptoms and the limited access to diagnostic methods could
have contributed to the high prevalence of presumptive
opportunistic infections and may have impaired the recognition of
non-opportunistic AIDS-defining neurological disorders.
A larger, multicenter study to analyze the temporal trends of
the neurological disease in HIV/AIDS patients in Brazil and its
changing profile is warranted. In addition, earlier HIV testing,
diagnosis and proper follow-up, including primary prophylaxis
for opportunistic infections and HAART, should be emphasized
as public health policies for the treatment and prevention of AIDS
in Brazil and other developing countries.
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